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Abstract
High MYC expression is linked to proliferative activity in most normal tissues and in cancer. MYC also supports self-renewal and proliferation of many types of tissue progenitor cells. Cancerous inhibitor of PP2A (CIP2A) promotes MYC phosphorylation and activity during intestinal crypt regeneration in vivo and in various cancers. CIP2A also supports male germ cell proliferation in vivo. However, the role of MYC in normal germ cell proliferation and spermatogonial progenitor self-renewal is currently unclear. Here, we demonstrate that male germ cells are CIP2A-positive but lack detectable levels of MYC protein; whereas MYC is highly expressed in Leydig cells and peritubular myoid cells contributing thereby to the testicular stem cell niche. On the other hand, MYC was co-expressed with CIP2A in testicular cancers. These results demonstrate that CIP2A and MYC are spatially uncoupled in the regulation of spermatogenesis, but functional relationship between these two human oncoproteins is established during testicular cancer transformation. We propose that further analysis of mechanisms of MYC silencing in spermatogonial progenitors may reveal novel fundamental information relevant to understanding of MYC expression in cancer.
Highlights
Animal reproduction is entirely dependent on adult germ cell proliferation
Based on (a) expression and functional role of Cancerous inhibitor of phosphatase 2A (PP2A) (CIP2A) in spermatogonia (Ventel _2012[3]), (b) the established functional link between CIP2A and MYC (Myant 2015[2]), and (c) the role of both CIP2A and MYC in regulating progenitor cell fate (Ventel _2012[3])(Myant 2015[2])(Wilkins 2008[4]), we assessed the status of MYC in spermatogonial progenitor cells, spermatogonia
While the testicular interstitial tissue was strongly immunopositive for MYC, its expression was not detected in the germ cells which were CIP2A positive (Figure 1A, B)
Summary
Animal reproduction is entirely dependent on adult germ cell proliferation. A special mode of proliferation, the self-renewal of tissue-specific stem - and progenitor cells is required both to support the renewal of tissues and for the rapid production of sperm. The Experimental Animal Committee of the University of Turku approved all protocols used in animal experiments (ESLH-2007-08517). Self-renewal involved in normal spermatogenesis and in the context of testicular cancers could reveal causal mechanisms generally relevant for cellular transformation. CIP2A promotes spermatogenesis by supporting maintenance of spermatogonial progenitor pool (Ventel _2012[3]), and facilitates intestinal crypt progenitor-driven intestinal regeneration in vivo (Myant 2015[2]). Whereas the latter was shown to involve CIP2A-mediated regulation of MYC (Myant 2015[2]), the expression and functional role for MYC in spermatogonial progenitors is poorly understood
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